Consumers continually seek to improve the appearance of their skin and in particular to reduce visible signs of skin aging. Unwanted signs include lines and wrinkles, skin sagging or atrophy, and loss of suppleness, and there remains a need for products that combat such signs of aging and, more generally, that provide anti-aging and/or anti-wrinkle effects.
Recent studies have revealed that dermal fibroblasts undergo morphology changes and cell body collapse in both chronically and photo-aged skin. See, e.g., Varani et al., 2004. J. Invest. Dermatol. 122:1471-9; and Varani et al., 2006. Am. J. Pathol. 168: 1861-8. Such alterations can lead to coarse, rough, and wrinkled appearance, which are characteristics of aged skin. Further studies suggest that collagen degradation along with altered integrin and focal adhesion molecules are factors contributing to the loss of a functional dermal collagen matrix, with the consequence of cell body collapse due to a loss of mechanical tension between fibroblasts and the matrix. See, e.g., Fisher et al., 2008. Arch Dermatol. 144: 666-72.
Paxillin is an important adaptor protein that mediates transmembrane integrins and growth factor signaling. It transduces messages from the extracellular matrix, recruits other focal adhesion molecules to form complexes, and activates intracellular cytoskeleton assembly. Brown et al., 2004. Physiol Rev. 84:1315-39. This process is important for cell adhesion and migration, as well as muscle contraction. Paxillin-mediated signaling also affects long-term changes in gene expression, cell proliferation, and extracellular matrix organization, which is important to wound repair and tissue regeneration.
Paxillin exists in higher eukaryotes as three isoforms. Paxillin a is the principle, ubiquitously expressed isoform, expressed in most adult human tissues other than brain; paxillin β- and γ-isoforms are restrictively expressed. A fourth isoform, paxillin δ, is found mainly in epithelial cells. The paxillin proteins are comprised of multiple protein-binding motifs, corresponding to multiple protein-protein interaction and protein recognition sites, with many phosphorylation sites dispersed throughout the molecule. Paxillin binding partners range from structural actin-binding proteins, such as vinculin, to signaling molecules such as focal adhesion kinase (FAK) and integrin-linked kinase (ILK). Paxillin is phosphorylated at the multiple tyrosine, serine, and threonine sites in response, e.g., to cell adhesion and/or various soluble growth factors and cytokines and is thought to be at the signaling crossroads of cell adhesion and growth factor modulation under normal conditions.
Following exposure to oxidative stress, abnormalities have been observed in paxillin phosphorylation and cytoskeletal organization in cultured cells. Hao et al., 2006. Free radical Biol Med. 41: 302-10; and Zhou et al., 1999. J Cell Physiol. 180: 182-9. Also, altered levels and altered localization of various focal adhesion proteins have been observed in senescent cells in vitro. Nishio et al., 2005. Histochem cell biol. 123:263-73. Nonetheless, no direct relation has been implicated between paxillin expression and visible signs of aging in human skin.
It is therefore an object of the invention to provide new approaches for combating signs of skin aging through paxillin-mediated pathways. It is a further object of the invention to provide new compositions and methods directed thereto. It is a still further object of the invention to improve the overall appearance of skin, including treating, reversing, and/or preventing signs of aging, using cosmetic compositions comprising effective amounts of one or more compounds that affect paxillin production.
The foregoing discussion is presented solely to provide a better understanding of nature of the problems confronting the art and should not be construed in any way as an admission as to prior art nor should the citation of any reference herein be construed as an admission that such reference constitutes “prior art” to the instant application.